c-Jun N-terminal kinase 1 interacts with and negatively regulates Wnt/beta-catenin signaling through GSK3beta pathway.
Increasing evidence shows that there is an interaction between mitogen-activated protein kinase and Wnt signaling and that their interaction plays important roles in a variety of cellular processes. However, how the two signaling interacts is not clear. In this study, we found that beta-catenin expression was strikingly increased in the intestinal normal mucosa and tumors of c-Jun N-terminal kinase (JNK) 1-deficient mice by immunohistochemical staining and that both beta-catenin expression and transcriptional activity were significantly upregulated in JNK1-deficient mouse embryonic fibroblasts. However, active JNK1 significantly inhibited beta-catenin expression and suppressed beta-catenin-mediated transcriptional activity by enhancing glycogen synthase kinase 3beta (GSK3beta) activity. But beta-catenin inhibition was significantly reduced by GSK3beta RNA interference or GSK3beta inhibitor lithium chloride and proteasome inhibitor MG132. Further, mutant beta-catenin at the phosphorylation sites of Ser33 and Ser37 by GSK3beta was resistant to activated JNK1-induced beta-catenin degradation. Moreover, the physical interaction between JNK1 and beta-catenin was detected by immunoprecipitation, and their colocalization was seen in cellular nuclei and cytoplasm. Taken together, our data provide direct evidence that JNK1 interacts with and negatively regulates beta-catenin signaling through GSK3beta pathway and that the beta-catenin alteration is probably responsible for the intestinal tumor formation in JNK1-deficient mice.
Hu
Dong
D
Department of Pathology, University of Illinois at Chicago, Chicago, IL 60612, USA.
Fang
Wenfeng
W
Han
Anjia
A
Gallagher
Lindsay
L
Davis
Roger J
RJ
Xiong
Bin
B
Yang
Wancai
W
D000818:Animals; D015153:Blotting, Western; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic / Q000378:metabolism; D005455:Fluorescent Antibody Technique; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism*; D006801:Humans; D007150:Immunohistochemistry; D007413:Intestinal Mucosa / Q000378:metabolism; D007414:Intestinal Neoplasms / Q000378:metabolism; D051379:Mice; D008817:Mice, Mutant Strains; D048055:Mitogen-Activated Protein Kinase 8 / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*; D014162:Transfection; D051153:Wnt Proteins / Q000378:metabolism*; D051176:beta Catenin / Q000378:metabolism*
D051153:Wnt Proteins; D051176:beta Catenin; D048055:Mitogen-Activated Protein Kinase 8; D038362:Glycogen Synthase Kinase 3